High molecular weight polyesterpolycarbonates and the use thereof for the preparation of bioerosible matrices

ABSTRACT

Polyesterpolycarbonates of formula (I) ##STR1## wherein a is an integer from 2 to 300; R 1  and R 2 , which can be the same or different, are each a polyester residue of formula (II) ##STR2## with x and y being integers from 0 to 100, and the ratio of (x/x+y)*100 being between 0 and 100, with the proviso that x and y are not 0 at the same time; R 3  and R 4  being aliphatic hydrocarbon residues of 1 to 4 carbon atoms; R 5  being an aliphatic hydrocarbon residue having from 2 to 18 carbon atoms or a cycloaliphatic hydrocarbon residue having from 3 to 8 carbon atoms; or a polyoxyalkylene residue of formula (III): ##STR3## wherein R 6  is hydrogen or methyl, n is an integer from 1 to 3 and m is an integer from 1 to 200; and the two --R 3  --COO and --R 4  --COO groups are randomly distributed in the polyester residue, with the polyesterpolycarbonates of formula (I) having an intrinsic viscosity of greater than 0.45 dl/g when measured in chloroform at 32° C. and being useful as bioerosible matrices for the controlled release of drugs.

The present invention relates to polyesterpolycarbonates of generalformula (I) ##STR4## wherein a is an integer from 2 to 300; R₁ and R₂,which can be the same or different, are each a polyester residue offormula (II) ##STR5## wherein x and y are integers from 0 to 100, theratio (x/x+y)*100, being comprised between 0 and 100, with the provisothat x and y are not 0 at the same time; R₃ and R₄, which can be thesame or different, are each a straight or branched chain aliphatichydrocarbon residue having from 1 to 4 carbon atoms; R₅ is a straight orbranched chain aliphatic hydrocarbon residue having from 2 to 18 carbonatoms or a cycloaliphatic hydrocarbon residue having from 3 to 8 carbonatoms, optionally bearing one or more straight or branched alkylsubstituents; or it is a polyoxyalkylene residue of formula (III):##STR6## wherein: R₆ is hydrogen or methyl, n is an integer from 1 to 3and m is an integer from 1 to 200; the two --R₃ --COO and --R₄ --COOgroups being randomly distributed in the polyester residue, with theproviso that the polyesterpolycarbonates of formula (I) have intrinsicviscosity not lower than 0.45 dl/g.

Generally, the polymers used as carriers for controlled release drugsmust be biocompatible, non toxic, free from impurities. Particularly,biodegradable polymers must give non-toxic, non-cancerogenic,non-teratogenic degradation products and must be easily eliminated.

The factors which affect biodegradability are chemical structure,morphology and particle size. Among these factors, crystallinity playsan important role, in view both of biodegradability and technology ofpolymer processing.

The common microencapsulation techniques comprise coacervation,evaporation of the emulsified solvent, coextrusion. The latter is thepreferred technique since it avoids the use of solvents and accordinglyimplies no toxicologic problems due to solvent residues.

Extrudible polymers must be stable at the coextrusion temperature, havea softening point nor too high, to avoid drug decomposition, nor toolow, to avoid storage problems.

Examples of pharmaceutical formulations, in which the drug (activeingredient) is incorporated in a biodegradable matrix, are well known inthe art. Reference may be made to "Biodegradable Polymers as DrugDelivery Systems", ed. by M. Chasin and R. Langer, Marcel Drekker Inc.,Orlando, Fla., 1985; "Formes Pharmaceutiques Nouvelles", P. Buri, F.Puisieux, E. Dalker, J. P. Benoit, Technique and documentation(Lavoisier), Paris, 1985; "Biodegradable Polymers for controlled Releaseof Peptides and Proteins", F. G. Hutchison and B. J. A. Furr, in DrugCarrier Systems, F. H. D. Roerdink and A. M. Kroom eds., John Wiley andSons, Chichester, 1989; "Controlled Release of Biologically ActiveAgents" Richard Baker, John Wiley and Sons, New York, 1987.

Different kinds of polymers have been used for the above purposes andamong these polycarbonates showed appropriate biocompatibilitycharacteristics. Kawaguchi et al. (Chem. Pharm. Bull. vol. 31, n. 4,1400-1403, 1983) disclose the biodegradability of polyethylene carbonateand polypropylene carbonate tablets and the possibility to obtainbiocompatible materials having programmed degradation by suitablyadmixing the two polycarbonates.

Polycarbonates have been well known for a long time. Aliphaticpolycarbonates are well known for example from DE 2546534, published onApr. 28, 1977, JP 6224190, published on Oct. 22, 1987, JP 1009225,published on Jan. 12, 1989, which provide them as plastifying agents andintermediates for the preparation of polyurethanes (see also U.S. Pat.No. 4,105,641, issued Aug. 8, 1978).

Also polycarbonates having homo- and copolymeric nature have beenproposed.

In U.S. Pat. No. 4,716,203 (American Cyanamid), issued on Dec. 29, 1987,diblock and triblock copolymers are disclosed, having a first block ofglycolic acid ester linked with trimethylene carbonate; triblockcopolymers have an intermediate block obtained from ethylene oxidehomopolymer or ethylene oxide-cyclic ether copolymer, otherwise frommacrocyclic ether copolymers. Said copolymers are bioabsorbable and areindicated for the final finishing of synthetic surgical threads.

International Patent Application WO 8905664 (Allied-Signal Inc.),published on Jun. 29, 1989, discloses medical devices partly or whollyformed by polycarbonates homopolymers or copolymers, which may containpolyether-polyamino moieties in the polymeric chain.

EP-A-0427185 (Boehringer Ingelheim), published on Jan. 15, 1991,discloses copolymers obtained from trimethylene carbonate and opticallyinactive lactides, useful for the manufacturing of surgical grafts.Chemically, the copolymers disclosed by Boehringer arepolyesterpolycarbonates and are obtained by two distinct processes: aone-step process, resulting in random copolymers, and a two-stepprocess, resulting in block copolymers. The block copolymers consist ofa polycarbonate block, resulting from the first process step, which asecond polyester block is linked to (see Example 17). The resultingbasic structure is described by the following formula (A) ##STR7##wherein D and E are hydrocarbon residues, p and q indicate the length ofthe block. By comparing formula (A) and formula (I) of the presentinvention, the different distribution of the carbonic and carboxylicester functions in the polymeric structures can be observed.

International Patent Application WO 9222600, published on Dec. 23, 1992,in the applicant's name, discloses randomized polyesterpolycarbonateblock copolymers of formula (I) useful as bioerosible matrices. But thecopolymers therein disclosed are not capable of achieving molecularweight and viscosity higher than a determined value, thus limiting theiruse as bioerosible matrices, making the workability difficult. Thecopolymers disclosed in this reference are prepared starting from amixture containing the hydroxyacids necessary for the formation of thepolyester block and a determined amount of a diol as to obtain apolyester oligomer bearing two hydroxylic functions at its ends. Theresulting intermediate is then reacted with carbonyldiimidazole, givingthe corresponding diimidazolyl formate, which is then reacted with thedesired diol to obtain the final polycarbonate. Through this process itis possible to obtain copolymers having a maximum viscosity of 0.45 dl/g(see Examples), but it is not possible to achieve higher values.

It has now been found that by means of a new process it is possible toobtain copolymers of formula (I) having viscosities higher than 0.45dl/g.

Such a process is a further object of the present invention, togetherwith the high molecular weight polymers obtained therefrom. The presentinvention is therefore a selection invention of WO 9222600.

In a first embodiment of the present invention, said process comprises:

a) reaction under vacuum of a mixture of hydroxyacids of formula (IV)and (V) ##STR8## wherein R₃ and R₄ are as defined above, to give thepolyester oligomer (VI) ##STR9## wherein R₃, R₄, x and y are as definedabove;

b) reaction of the polyester (VI) with bis-chloroformate of formula(VIII) ##STR10## wherein R₅ is as defined above; optionally in thepresence of a tertiary amine, at a temperature ranging from -10° to 50°C.; preferably from 0° to 30° C.; and subsequent application of vacuum(pressure from 5 to 0,001 mmHg, preferably from 1 to 0.1 mmHg).

According to this first embodiment of the invention, high molecularweight polyesterpolycarbonates of formula (I), having viscosity higherthan 0.45 dl/g, are obtained.

The starting materials are commercially available, anyway they aredescribed in the chemical literature.

The preparation of the polyester (VI) occurs under inert atmosphere, forexample in an inert gas, such as nitrogen or argon, at a temperatureranging from 170° to 220° C.; preferably from 180° to 200° C.; for atime of 15-30 hours, preferably 20-25 hours. After that, an in vacuoreaction step follows at a vacuum value of 5 to 0.001 mmHg, preferablyless than 1 mmHg, for the same time and at the same temperature.

After in vacuo step, the oligomer is cooled while maintaining vacuum andit is isolated by precipitation from chloroform/ethyl ether.

Subsequently, the oligomer is reacted with the bischloroformate (VIII)in a chlorinated solvent at a temperature ranging from 0° C. to roomtemperature, optionally in the presence of a tertiary amine, for aperiod of time ranging from 4 to 30 hours, preferably 15-20 hours.

According to a second embodiment of the present invention, the processcomprises the in situ formation of the bischloroformate by reactingphosgene with a diol of formula (X)

    HO--R.sub.5 --OH                                           (X)

wherein R₅ is as above defined, to give the correspondingbischloroformate, which is then reacted with a polyester oligomer offormula (VI) ##STR11## wherein R₃, R₄, x and y are as defined above,optionally in the presence of one or more tertiary amines, and asubsequent in vacuo application step to give the polymer of formula (I).

According to a third embodiment of the present invention, a polyesteroligomer of formula (VI) ##STR12## wherein R₃, R₄, x and y are asdefined above, is reacted with phosgene to give chloroformate of formula(IX), ##STR13## wherein R₃ and R₄ are as defined above, which is thenreacted with a diol of formula (X)

    HO--R.sub.5 --OH                                           (X)

wherein R₅ is as above defined, to give the polymer of formula (I).

Preferably, the reaction between (VI) and (IX) is carried out in thepresence of a tertiary amine.

The final polymerization step is carried out under the same conditionsas above.

In a further preferred embodiment of the present invention, in thepolyesterpolycarbonates of formula (I), the polyester residue of formula(II) is a lactic acid-glycolic acid polyester in 1:1 molar ratio; R₁ andR₂ are alkylene chains having from 2 to 12 carbon atoms.

Advantageously, the process according to the present invention allowsalso the preparation of low molecular weight polyesterpolycarbonatesdisclosed in WO 9222600.

The polymers obtainable by the process of the present invention havehigh viscosity, higher than that of the polymers disclosed in WO9222600.

The polymers of the present invention have advantageous physico-chemicalproperties which make them suitable for use as bioerosible matrices.Particularly, these polymers have low crystallinity and such a propertygives them good biodegradability and workability characteristics, inparticular in the coextrusion technology.

Therefore, the use of the above described polyesterpolycarbonates forthe preparation of bioerosible matrices is another object of the presentinvention.

In another aspect thereof, the present invention provides pharmaceuticalcompositions for the controlled release of the active principle frombioerosible matrices comprising polyesterpolycarbonates of formula (I).

The following examples further illustrate the invention.

EXAMPLE 1

243.33 g of a 72% lactic acid aqueous solution and 151.15 g of 99%glycolic acid were placed into a three-necked flask, equipped with aDean-Starck apparatus, under anhydrous nitrogen atmosphere. The mixturewas maintained under nitrogen stream and stirred at the temperature of200° C. for 24 hours. Vacuum was then applied (<1 mmHg) for 24 hours atthe same temperature. After cooling under vacuum, dissolving inchloroform (2 ml of chloroform per g of polymer) and precipitating inethyl ether, 266.77 g of oligomer were thus obtained with anumber-average molecular weight 1,870 (evaluated by titration in benzylalcohol with a 0.1N standard solution of tetrabutylammonium hydroxide inisopropanol) and an intrinsic viscosity of 0.105 dl/g.

EXAMPLE 2

With a procedure similar to the one of example 1, 243.33 g of a 72%lactic acid aqueous solution and 50.38 g of 99% glycolic acid werereacted. 169.88 g of oligomer were thus obtained with a number-averagemolecular weight 2560 (evaluated by titration in benzyl alcohol with a0.1N standard solution of tetrabutylammonium hydroxide in isopropanol)and an intrinsic viscosity of 0.13 dl/g (chloroform at 32° C.).

EXAMPLE 3

With a procedure similar to the one of example 1, 243.33 g of a 72%lactic acid aqueous solution were reacted. 102 g of oligomer were thusobtained with a number-average molecular weight 2320 (evaluated bytitration in benzyl alcohol with a 0.1N standard solution oftetrabutylammonium hydroxide in isopropanol) and an intrinsic viscosityof 0.12 dl/g (chloroform at 32° C.).

EXAMPLE 4

243.33 g of a 72% lactic acid aqueous solution and 151.15 g of 99%glycolic acid were placed into a three-necked flask, equipped with aDean-Starck apparatus, under anhydrous nitrogen atmosphere. The mixturewas maintained under nitrogen stream and stirred at the temperature of200° C. for 24 hours. After cooling under vacuum, dissolving inchloroform (2 ml of chloroform per g of polymer) and precipitating inethyl ether, 244.5 g of oligomer were thus obtained with anumber-average molecular weight 455 (evaluated by titration in benzylalcohol with a 0.1N standard solution of tetrabutylammonium hydroxide inisopropanol).

EXAMPLE 5

49.44 g of a oligomer, a 1:1 molar ratio lactic acid-glycolic acidcopolymer (PLGA 1:1), having number-average molecular weight 1,873(intrinsic viscosity of 0.096 dl/g) and 81.4 ml of amylane-stabilizedand calcium hydride-dried chloroform were placed into a 500 mltwo-necked flask, under anhydrous nitrogen atmosphere. After completedissolution of the oligomer, N-ethyldiisopropylamine (98% w/w titre) and3.29 g of 4-dimethylaminopyridine (99% w/w titre ) were added. Aftercooling the mixture to 0° C., 5.64 ml of triethylene glycolbischloroformate (97% w/w titre) were dropped within 5 minutes. Themixture was maintained at 0° C. for 4 hours, then warmed to roomtemperature (20°-25° C.) within two hours, and kept at this value forfurther 10 hours. A concentration step of the reaction medium was thencarried out by evaporating off the solvent under vacuum (<1 mmHg, T-20°C., 2 hours). The resulting solid was taken up with chloroform andprecipitated in ethyl ether. After a further precipitation of thepolymer in isopropyl alcohol and extraction in isopropyl ether, 45 g ofa polymer having intrinsic viscosity of 0.729 dl/g at 32° C. inchloroform were obtained.

EXAMPLE 6

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,873 (intrinsic viscosity of 0.096dl/g) and 6.48 g of 1,6-hexanediol bischloroformate (97% w/w titre) werereacted. 47.5 g of a polymer having intrinsic viscosity of 0.576 dl/gwere obtained.

EXAMPLE 7

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,873 (intrinsic viscosity of 0.096dl/g) and 5.74 g of 1,4-butanediol bischloroformate were reacted. 48.25g of a polymer having intrinsic viscosity of 0.626 dl/g were obtained.

EXAMPLE 8

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,873 (intrinsic viscosity of 0.096dl/g) and 8.51 g of tetraethylene glycol bischloroformate were reacted.49.3 g of a polymer having intrinsic viscosity of 0.727 dl/g wereobtained.

EXAMPLE 9

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 3:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 3:1), havingnumber-average molecular weight 1,905 (intrinsic viscosity of 0.102dl/g) and 8.55 g of tetraethylene glycol bischloroformate were reacted.50.4 g of a polymer having intrinsic viscosity of 0.675 dl/g wereobtained.

EXAMPLE 10

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,873 (intrinsic viscosity of 0.096dl/g) and 6.16 g of diethylene glycol bischloroformate were reacted.47.5 g of a polymer having intrinsic viscosity of 0.658 dl/g wereobtained.

EXAMPLE 11

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,873 (intrinsic viscosity of 0.096dl/g) and 14.0 g of polyethylene glycol 400 bischloroformate werereacted. 52.4 g of a polymer having intrinsic viscosity of 0,582 dl/gwere obtained.

EXAMPLE 12

With a procedure similar to the one of example 5, 49.94 g of a oligomer,a 1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,873 (intrinsic viscosity of 0.096dl/g) and 19.33 g of polyethylene glycol 600 bischloroformate werereacted. 58.5 g of a polymer having intrinsic viscosity of 0.527 dl/gwere obtained.

EXAMPLE 13

15 g of PLGA 1:1 (number-average molecular weight 1,565) and 27.25 ml ofchloroform were placed into a 250 ml two-necked flask, under anhydrousnitrogen atmosphere. After cooling the mixture at 0° C., 16.67 ml of atoluene solution of phosgene (1.93M) were added. After three hours at 0°C., 1.1 ml of tetraethylene glycol, 2.81 ml of N-ethyldiisopropylamineand 0.993 g of 4-dimethylaminopyridine were added. After two hours thetemperature was warmed to 25° C. and kept at this value for 14 hours.The reaction mixture was then concentrated for 2 hours under vacuum (<1mmHg), taken up with 20 ml of chloroform and precipitated in ethylether. 14.2 g of a polymer having viscosity of 0.12 dl/g were obtained.

EXAMPLE 14

21.74 ml of a toluene solution of phosgene (1.93M) were introduced in athree-necked flask, equipped with a dropping funnel, under anhydrousnitrogen atmosphere. After cooling down to 0° C., a solution containing2.24 ml of triethylene glycol, 9 ml of chloroform, 5.74 ml ofN-ethyldiisopropylamine and 2:02 g of 4-dimethylaminopyridine wasdropped therein. After 20 minutes phosgene excess was removed bybubbling nitrogen, and a solution containing PLGA 1:1 (number-averagemolecular weight 1,865, intrinsic viscosity of 0.099 dl/g) , 54.9 ml ofchloroform, 5.74 ml of N-ethyldiisopropylamine and 2.02 g of4-dimethylaminopyridine was dropped therein. The mixture was maintainedat 0° C. for 4 hours, then warmed to room temperature, and kept at thisvalue for 12 hours. The reaction mixture was then concentrated for 4hours under vacuum (<1 mmHg), taken up with chloroform and precipitatedin ethyl ether. After a further precipitation in isopropyl alcohol andextraction in isopropyl ether, 29.5 g of a polymer having intrinsicviscosity of 0.782 were obtained.

EXAMPLE 15

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,865 (intrinsic viscosity of 0.097dl/g) and 1.90 g of 1,6-hexanediol were reacted. 28.5 g of a polymerhaving intrinsic viscosity of 0.543 dl/g were obtained.

EXAMPLE 16

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,865 (intrinsic viscosity of 0.097dl/g) and 1.44 g of 1,4-butanediol were reacted. 26.9 g of a polymerhaving intrinsic viscosity of 0.631 dl/g were obtained.

EXAMPLE 17

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,865 (intrinsic viscosity of 0.097dl/g) and 3.12 g of tetraethylene glycol were reacted. 27.4 g of apolymer having intrinsic viscosity of 0.758 dl/g were obtained.

EXAMPLE 18

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,865 (intrinsic viscosity of 0.097dl/g) and 1.70 g of diethylene glycol were reacted. 27.2 g of a polymerhaving intrinsic viscosity of 0. 697 dl/g were obtained.

EXAMPLE 19

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,865 (intrinsic viscosity of 0.097dl/g) and 6.43 g of polyethylene glycol 400 were reacted. 30.5 g of apolymer having intrinsic viscosity of 0.689 dl/g were obtained.

EXAMPLE 20

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,865 (intrinsic viscosity of 0.097dl/g) and 9.65 g of polyethylene glycol 600 were reacted. 35.8 g of apolymer having intrinsic viscosity of 0.624 dl/g were obtained.

EXAMPLE 21

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,920 (intrinsic viscosity of 0.098di/g) and 15.62 g of polyethylene glycol having average molecular weight1,000 were reacted. 44 g of a polymer having number-average molecularweight 239,000, weight-average molecular weight 434,000 (values referredto the polystyrene standards in chloroform) and an intrinsic viscosityof 1.740 dl/g were obtained.

EXAMPLE 22

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,920 (intrinsic viscosity of 0.098dl/g) and 31.25 g of polyethylene glycol having average molecular weight2,000 were reacted. 60 g of a polymer having number-average molecularweight 197,000, weight-average molecular weight 37,0000 (values referredto the polystyrene standards in chloroform) and an intrinsic viscosityof 1.552 dl/g were obtained.

EXAMPLE 23

With a procedure similar to the one of example 14, 20 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,920 (intrinsic viscosity of 0.098dl/g) and 41.60 g of polyethylene glycol having average molecular weight4,000 were reacted. 60.5 g of a polymer having number-average molecularweight 194,000, weight-average molecular weight 370,000 (values referredto the polystyrene standards in chloroform) and an intrinsic viscosityof 2.161 dl/g were obtained.

EXAMPLE 24

With a procedure similar to the one of example 14, 10 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,920 (intrinsic viscosity of 0.098dl/g) and 41.60 g of polyethylene glycol having average molecular weight8,000 of were reacted. 50 g of a polymer having number-average molecularweight 110,000, weight-average molecular weight 276,000 (values referredto the polystyrene standards in chloroform) and an intrinsic viscosityof 1.162 dl/g were obtained.

EXAMPLE 25

With a procedure similar to the one of example 14, 30 g of a oligomer, a1:1 molar ratio 1 actic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,920 (intrinsic viscosity of 30 0.098dl/g) and 15.62 g of polytetrahydrofuran having average molecular weight1,000 were reacted. 44 g of a polymer having an intrinsic viscosity of0.600 dl/g were obtained.

EXAMPLE 26

With a procedure similar to the one of example 14, 20 g of a oligomer, a1:1 molar ratio lactic acid-glycolic acid copolymer (PLGA 1:1), havingnumber-average molecular weight 1,920 (intrinsic viscosity of 0.098dl/g) and 41.60 g of polypropylene glycol having average molecularweight 4,000 were reacted. 60.0 g of a polymer having an intrinsicviscosity of 0.25 dl/g were obtained.

EXAMPLE 27

Microspheres of the oligomer having number-average molecular weight1,920 were prepared according to the following procedure. 0.60 g ofpolymer were dissolved in 8 ml of chloroform. The solution was slowlyadded to a 0.4% aqueous solution of polyvinyl alcohol having averagemolecular weight 20,000 the system was kept under stirring, at roomtemperature, for 2 hours with stirring rate of 750 rpm. The finalproduct was sieved humid. 120 mg of microspheres were obtained, having agranulometry of 68-125 micrometers.

EXAMPLE 28

With a procedure similar to the one of example 27, 95 mg of microsphereswere prepared, having granulometry from 68 to 125 micrometers, of acommercial polyester having the following characteristics: 75:25D,L-lactic acid/glycolic acid ratio, number-average molecular weight53,000, weight-average molecular weight 105,000 and intrinsic viscosityof 0.54 dl/g.

EXAMPLE 29

With a procedure similar to the one of example 27, 142 mg ofmicrospheres were prepared, having granulometry from 68 to 125micrometers, of the product obtained with the procedure of example 21.

EXAMPLE 30

With a procedure similar to the one of example 27, 222 mg ofmicrospheres were prepared, having granulometry from 68 to 125micrometers, of the product obtained with the procedure of example 22.

EXAMPLE 31

With a procedure similar to the one of example 27, 330 mg ofmicrospheres were prepared, having granulometry from 68 to 125micrometers, of the product obtained with the procedure of example 23.

EXAMPLE 32

With a procedure similar to the one of example 27, 58 mg of microsphereswere prepared, having granulometry from 68 to 125 micrometers, of theproduct obtained with the procedure of example 14.

EXAMPLE 33

Degradation of the microspheres prepared according to examples 28-33 wasevaluated placing microspheres samples (160 mg) into 5 ml of phosphatebuffer, pH-7.4, at a temperature of 37° C., checking the completedisappearance thereof by optical microscopy. The obtained data aresummarized in the following Table.

                  TABLE                                                           ______________________________________                                                         Days on which the                                                             microspheres                                                 Polymer          disappear completely                                         ______________________________________                                        Commercial PLGA  >32                                                          Polymer of example 21                                                                          >32                                                          Polymer of example 22                                                                          7                                                            Polymer of example 23                                                                          4                                                            Polymer of example 14                                                                          >32                                                          Oligomer with MW - 1,920                                                                       11                                                           ______________________________________                                    

The Table shows that according to the process of the inventioncopolymers having degradation times ranging within wide time intervalscan be obtained. Such intervals range from a few days to valuescomparable with those of commercial copolyesters, thus allowing toprepare systems having optimum degradation rates, depending on theapplication requirements.

We claim:
 1. A polyesterpolycarbonates of formula (I) ##STR14## whereina is an integer from 2 to 300; R₁ and R₂, which can be the same ordifferent, are each a polyester residue of formula (II) ##STR15##wherein x and y are integers from 0 to 100, the ratio (x/x+y)*100, beingcomprised between 0 and 100, with the proviso that x and y are not 0 atthe same time; R₃ and R₄, which can be the same or different, are each astraight or branched chain aliphatic hydrocarbon residue having from 1to 4 carbon atoms; R₅ is a straight or branched chain aliphatichydrocarbon residue having from 2 to 18 carbon atoms or a cycloaliphatichydrocarbon residue having from 3 to 8 carbon atoms, optionally bearingone or more straight or branched alkyl substituents; or apolyoxyalkylene residue of formula (III): ##STR16## wherein: R₆ ishydrogen or methyl, n is an integer from 1 to 3 and m is an integer from1 to 200; the two --R₃ --COO and --R₄ --COO groups being randomlydistributed in the polyester residue, with the polyesterpolycarbonatesof formula (I) having an intrinsic viscosity of greater than 0.45 dl/gwhen measured in chloroform at 32° C.
 2. A polyesterpolycarbonateaccording to claim 1, wherein the polyester residue of formula (II) is alactic acid-glycolic acid polyester in 1:1 molar ratio.
 3. Apolyesterpolycarbonate according to claim 1, wherein the intrinsicviscosity is at least about 1.162 dl/g.
 4. A polyesterpolycarbonateaccording to claim 1, wherein the intrinsic viscosity is at least about2.161 dl/g.
 5. A polyesterpolycarbonate according to claim 1, whereinthe x and y are each at least
 1. 6. A process for the preparation ofpolyesterpolycarbonates of formula (I) ##STR17## wherein a is an integerfrom 2 to 300; R₁ and R₂, which can be the same or different, are each apolyester residue of formula (II) ##STR18## wherein x and y are integersfrom 0 to 100, the ratio (x/x+y)*100, being comprised between 0 and 100,with the proviso that x and y are not 0 at the same time; R₃ and R₄,which can be the same or different, are each a straight or branchedchain aliphatic hydrocarbon residue having from 1 to 4 carbon atoms; R₅is a straight or branched chain aliphatic hydrocarbon residue havingfrom 2 to 18 carbon atoms or a cycloaliphatic hydrocarbon residue havingfrom 3 to 8 carbon atoms, optionally bearing one or more straight orbranched alkyl substituents; or a polyoxyalkylene residue of formula(III): ##STR19## wherein: R₆ is hydrogen or methyl, n is an integer from1 to 3 and m is an integer from 1 to 200; the two --R₃ --COO and --R₄--COO groups being randomly distributed in the polyester residue, themethod comprising the following steps:a) reacting under vacuum a mixtureof hydroxyacids of formula (IV) and (V) ##STR20## wherein R₃ and R₄ areas defined above, giving the polyester oligomer (VI) ##STR21## whereinR₃ and R₄, x and y are as defined above; b) reacting polyester (VI) withbis-chloroformate of formula (VIII) ##STR22## wherein R₅ is as definedabove; optionally in the presence of one or more tertiary amines, and asubsequent vacuum application step.
 7. A process according to claim 6,wherein a diol of formula (X)

    HO--R.sub.5 --OH

wherein R₅ is as defined above, is reacted with phosgene to produce acorresponding bis-chloroformate, which is then reacted with a polyesteroligomer of formula (VI) ##STR23## wherein R₃, R₄, X and y are asdefined above, optionally in the presence of one or more tertiary aminesand a subsequent vacuum application step, to produce the polymer offormula (I).
 8. A process according to claim 6 wherein a polyesteroligomer of formula (VI) ##STR24## wherein R₃, R₄, x and y are asdefined above, is reacted with phosgene to give the chloroformate offormula (IX), ##STR25## wherein R₃ and R₄ are as defined above, which isthen reacted with a diol of formula

    HO--R.sub.5 --OH

wherein R₅ is as defined above, to produce the polymer of formula (I).9. A polyesterpolycarbonate obtained by the process of claim
 6. 10. Abioerosible matrix comprising a polyesterpolycarbonate according toclaim 9 and an active principle.
 11. A pharmaceutical product comprisingmicrospheres of the bioerosible matrix according to claim
 10. 12. Abioerosible matrix comprising a polyesterpolycarbonate according toclaim 1 and an active principle.
 13. A pharmaceutical product comprisingmicrospheres of the bioerosible matrix according to claim 12.